Role of the Lyn Tyrosine Kinase in the Development of Autoimmune Disease

International Journal of Review Clinical Rheumatology Tsantikos, Gottschalk, Maxwell & Hibbs Role of the Lyn tyrosine kinase in the development of autoimmune disease 9 Review Role of the Lyn tyrosine kinase in the development of autoimmune disease Int. J. Clin. Rheumatol. The Lyn tyrosine kinase plays a key regulatory role in the immune system that was first Evelyn Tsantikos1, Timothy highlighted by the phenotype of Lyn-/- mice. These animals develop an autoimmune A Gottschalk1, Mhairi J disease similar to the autoimmune disorder systemic lupus erythematosus. Maxwell1 & Margaret L ,1 Deregulation of the Lyn pathway is also observed in lupus patient samples, validating Hibbs* 1Leukocyte Signalling Laboratory, Lyn-/- mice as a model of lupus, as well as providing an archetype for the testing of Department of Immunology, suitable therapeutic agents. Here, we present an overview of the role of Lyn in immune Monash University, Alfred Medical cells and autoimmunity, emphasizing the pathogenic mechanisms contributing to Research & Education Precinct, autoimmune disease in Lyn-/- mice and the deregulation of Lyn-dependent pathways Melbourne, Victoria 3004, Australia in patients with lupus, and provide a perspective on the therapeutic targeting of *Author for correspondence: Tel.: +61 3 9903 0921 Lyn-regulated pathways in this disease. Fax: +61 3 9903-0038 [email protected] Keywords: autoimmune disease • glomerulonephritis • inflammation • lupus • Lyn Lyn tyrosine kinase: from historical is not expressed in T cells [9], except under perspective to role in immune cells very specific and artificial circumstances Lyn is one of nine members of the Src fam- [10–12] . SFKs are myristoylated, which local- ily of protein tyrosine kinases (SFKs). These izes them to the plasma membrane, in close enzymes are commonly associated with cell proximity to receptors and other signaling 10.2217/IJR.14.44 surface receptors that lack intrinsic kinase complexes [13] . In immune cells, SFK mem- activity [1] . Lyn was first described in 1987 bers including Lyn, are commonly associ- as an Lck/Yes-related novel tyrosine kinase ated with immunoreceptors and constitute a and hence its name was born [2]. Subsequent critical part of the signaling mechanism [14] . phylogenetic studies showed that Lyn is Upon receptor cross-linking, SFKs become evolutionarily most related to the hemato- activated and phosphorylate tyrosine residues 5 poietic SFK Hck [3]. The Lyn gene maps to on the receptor complex to recruit key signal- human chromosome 8q12.1 [2] and 4qA1 ing proteins, triggering a cascade of signaling in mice where a pseudo gene is also found events that lead to a physiological response [4]. Two Lyn proteins of 53 and 56 kDa are (e.g., activation or proliferation). Significant 2014 expressed and arise from alternate splicing homology exists between the SFKs and they of exon 2 [5,6]. The two isoforms of Lyn are are often co-expressed in the same cell. As found in mice, rats and humans and dif- such, functional redundancy is possible, and fer by only 21 amino acids in the enzyme’s indeed mouse knockout studies have shown N-terminal unique domain [7]. Both iso- that loss of one SFK may in some cases be forms are co-expressed, and only recently compensated for by another [15] . Early studies have studies began to unravel differences on Lyn focused on its properties relative to in their function [8]. The nucleotide and other members of the Src family who were amino acid sequences of the mouse, rat and known to initiate signaling cascades down- human Lyn genes have been reported and stream of co-associated immunoreceptors [16] are highly conserved [7]. Although Lyn is that induced cell proliferation and activation part of expressed widely in the immune system, it [17] . It was not until the generation of the 10.2217/IJR.14.44 © 2014 Future Medicine Ltd Int. J. Clin. Rheumatol. (2014) 9(5), 519–535 ISSN 1758-4272 519 Review Tsantikos, Gottschalk, Maxwell & Hibbs Lyn-/- mouse in the mid-1990s that a unique inhibitory interact with their binding partners, while the active role for Lyn was discovered, challenging the belief that protein tyrosine kinase (PTK) domain is able to phos- Lyn was primarily an activatory and pro-oncogenic Src phorylate its substrate (Figure 2B). Readers are referred kinase. Contrary to original expectations, Lyn-/- mice to the comprehensive review of Brown and Cooper on exhibited a progressive autoimmune disease reminis- the structure, regulation and substrates of SFKs [22]. cent of systemic lupus erythematosus (SLE; lupus) In addition to CD45 phosphatase, which can dephos- [18,19], and Lyn was subsequently found to be a signal- phorylate both the activatory and inhibitory tyrosine ing effector molecule in both activatory and inhibitory residues on Lyn [23,24], the SHP-1 phosphatase is impli- pathways (reviewed in [20]) (Figure 1). cated in negative regulation of Lyn activity via dephos- The kinase activity of SFKs is tightly controlled phorylation of the Lyn autophosphorylation site [25]. through regulated phosphorylation of two key tyrosine Mutating the C-terminal regulatory Tyr508 by replac- residues: in the case of Lyn, Tyr508 in the C-termi- ing it with a phenylalanine residue permanently locks nal ‘regulatory’ domain and the autophosphorylation the enzyme into an active state (Figure 2C). In this con- site in the kinase domain (Tyr397). At steady-state, stitutively active state Lyn-regulated proteins become the negative regulatory Tyr508 is phosphorylated by hyper-Tyr phosphorylated [26,27]. The crystal structure the tyrosine kinase c-Src kinase (Csk; [21]) and inter- of the kinase domain of Lyn has been reported and acts with Lyn’s own Src homology 2 (SH2) domain, closely resembles that of Src, Lck and Hck [28]. restraining the enzyme in a ‘closed’, inactive conforma- In B cells, Lyn is associated with the B-cell antigen tion (Figure 2A). Activation of Lyn occurs via dephos- receptor (BCR) complex [29,30], and is rapidly activated phorylation of Tyr508, as well as autophosphorylation upon BCR cross-linking [31] . Upon activation, Lyn is of Tyr397. This allows Lyn to adopt an ‘open’ con- able to phosphorylate tyrosine residues on immuno- formation, exposing SH2 and SH3 domains that can receptor tyrosine-based activation motifs (ITAMs) on Activatory receptor Inhibitory receptor SFK Lyn P I P P I P T P T P A P I P M P Syk P M P SHP-1 DOK SHIP-1 PI3K/MAPK/NF-κB Figure 1. Schematic representation of Lyn and the Src family of protein tyrosine kinases in immune cell signaling. The SFKs play an essential role in initiating activatory signaling from ITAM-containing immunoreceptors such as the BCR. While Lyn contributes to positive signaling, it also plays an essential nonredundant role in inhibitory signaling from ITIM-bearing inhibitory receptors. Solid lines signify positive signaling pathways, while dotted green lines indicate activatory signaling pathways that can also be regulated by Lyn. Dashed red lines specify inhibitory pathways that are regulated exclusively by Lyn. BCR: B-cell antigen receptor; ITAM: Immunoreceptor tyrosine-based activation motif; ITIM: Immunoreceptor tyrosine-based inhibition motif; SFK: Src family of protein tyrosine kinases. 520 Int. J. Clin. Rheumatol. (2014) 9(5) future science group Role of the Lyn tyrosine kinase in the development of autoimmune disease Review Homeostasis Transiently active Constitutively active SH3 P Proline-rich SH3 SH3 sequences P K275 E260 SH2 PTK P SH2 pY sequences SH2 Y508 Closed inactive ATP conformation K275 E260 K275 E260 ADP Kinase PTK PTK domain P Y397 Y397 Substrate P P Y508 F508 Open active Lynup/up conformation Kinase inactive Cytoplasmic SH3 P P G260 SH3 K275 P SH2 E260 SH2 PTK Y397 P ATP K275 Y508 Y508 PTK WeeB Lyn∆N, caspase cleaved Lyn Figure 2. Structure and conformation of the Src family of protein tyrosine kinases. Representative structure of the Src family of protein tyrosine kinases (SFKs) at (A) steady state; (B) when transiently active; (C) when rendered constitutively active through mutation of the C-terminal regulatory tyrosine as occurs in Lynup/up mice; (D) when rendered kinase-inactive such as in WeeB- or Mld4- mutant mice; and (E) when cytoplasmic as occurs in LynΔN mice. Key domains and amino acid residues indicated are: Src homology 2 (SH2) domain, SH3 domain and protein tyrosine kinase (PTK) domain; K275: ATP-binding site; Y397: autophosphorylation site; Y508: negative regulatory tyrosine; E260: site mutated in WeeB mice that renders Lyn kinase inactive. Ig-α and -β subunits of the BCR, which serve as sites to calcium flux, leading to survival and differentiation recruit additional effector molecules via SH2 domain pathways. The phosphorylation of ITAMs can also binding such as Syk (Figure 1) [32,33]. Once other effec- be performed by other SFKs, such as Fyn, leading tors are recruited to the plasma membrane, positive to redundancy among SFKs in activatory signaling signaling cascades are initiated that result in increased (Figure 1) [29,34–35]. However, the initiation of inhibi- future science group www.futuremedicine.com 521 Review Tsantikos, Gottschalk, Maxwell & Hibbs tory signaling cascades in B cells is a feature uniquely tibodies targeting nuclear antigens [51,53]. Autoreactive characteristic of Lyn. Lyn is able to phosphorylate IgG and IgA can be observed in mice as young as 8 tyrosine residues in immunoreceptor tyrosine-based weeks of age and progressively accumulates with age. inhibition motifs (ITIMs) in inhibitory receptors As described in Figure 3, a key feature of older mice such as FcγRIIb1, PIR-B and CD22 (Figure 1) [36–41]. is the expansion of the myeloid compartment, which Phosphorylated ITIMs serve as docking sites for SH2 gives rise to splenomegaly, inflammatory cytokine domain-containing inhibitory phosphatases such as imbalances, and T-cell hyperactivation, despite the the protein tyrosine phosphatase SHP-1 and the lipid fact that Lyn is not ordinarily expressed in T cells.

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